The long-term goal of the proposed research is to characterize factors that influence memory and neural deterioration in aging females. Aged and Alzheimer?s disease (AD) patients exhibit memory decline, which is related to deterioration of forebrain cholinergic neurons and projection areas such as hippocampus and cortex. AD is more prevalent in women, and female rats show an earlier and more-extreme age-related memory decline than males. This exaggerated memory loss may be related to ovarian hormone decline. Indeed, ovariectomy (Ovx) compromises cholinergic neuron integrity and nerve growth factor (NGF) levels. Other research suggests a relationship between estrogen and beta-amyloid, the main constituent of plaques seen in AD. These effects may provide a biological explanation for data showing that Ovx results in memory decline. Such an interactive hypothesis has not been directly tested. We propose to test, in aging female rats, whether Ovx exacerbates age-related changes in cortical, forebrain, and hippocampal cholinergic neurons, NGF, and amyloid precursor protein (APP). Further, although estrogen replacement improves memory and decreases risk of heart disease, stroke, and AD in menopausal women, it is controversial since it also increases cancer risk. Raloxifene is a SERM that acts as an estrogen antagonist in breast and uterus, but an agonist in lipid and bone. Since raloxifene increased neurite growth in a cell line and ChAT activity in the hippocampus in Ovx rats, it may also improve memory. We propose to test whether raloxifene, like estrogen, affects working and reference memory, forebrain cholinergic cell integrity, NGF, and APP in aging female rats. Since there is no known cure for AD, we hope that this type of interdisciplinary research will aid in the discovery of new and more efficacious therapies.